Cabazitaxel is chemically also known as (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate (I).

It is approved in USFDA as JEVTANA™ and is chemically mentioned in the label as (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy-carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate—propan-2-one (1:1) solvatomorph (Cabazitaxel:acetone). Cabazitaxel is a white to off-white crystalline powder and is lipophilic in nature, practically insoluble in water.
Bouchard et at in U.S. Pat. No. 5,847,170 provides the first disclosure of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy-carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate (also known as Cabazitaxel), which also describes the process for preparing Cabazitaxel.
Kung Liang-Rern et at in U.S. 2012149925A1 disclose process for preparing Cabazitaxel by reacting beta-lactam side chain with a protected baccatin derivative in the presence of one or more Lewis acids and a base agent, wherein Lewis acid may be selected from LiBr, MgBr2, CsBr, ZnBr2, ZnCl2, CuBr, Cu(CF3SO4)2, BF3.OEt2, KBr, TiCl4, SnCl2, ScCl3, VCl3, AlCl3, InCl3, Al2CO3, CeCl3, Ag2O, ZnClO4, LiClO4, Ti{OCH(CH3)2}4 or any combination thereof.
According to applicant of U.S. 20120149925A1, use of Lewis acid is one of inventive merit of the application. Applicant in the specification mentions that—comparing to the reaction carried out without Lewis acid, the presence of Lewis acid provides a more selective reaction, characterized by higher reaction rate, higher yield, more selective product, higher purity of the desired product and less side products.
Other disclosures related to Cabazitaxel process viz,—CN102532065A, CN102675256A and CN1023367268 also disclose similar processes however, either involving organometallic bases selected from n-BuLi, NaHMDS, KHMDS, KH & NaH and extremely low temperature conditions for the coupling reaction or different protecting groups on beta lactam side chains with varying bases and extremely low temperature conditions.
Subsequent to process of Cabazitaxel, the concern has remained for the solid form isolated for Cabazitaxel. As mentioned earlier, the Cabazitaxel form mentioned in the label as (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy-carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate—propan-2-one (1:1) solvatomorph (Cabazitaxel: acetone)is designated as Form-A in EMEA scientific discussion as well as in the subsequent patent U.S. Pat. No. 7,241,907.
Further, it appears from the literature that in order to achieve therapeutic role, it is Cabazitaxel base molecule that has to play the role and not necessarily its solvates as long as stable solvate or base form known to exists. In line with this, applicant in US 20120301425A1 (Eq. WO 2011051894A1) on page 2 mentions that Cabazitaxel may be administered in base form (cf. above formula), or in the form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone solvate, and, more particularly, may be the solvate described in WO 2005/02846. It may be an acetone solvate of cabazitaxel containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means content of acetone/content of acetone+cabazitaxelx100). An average value of the acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of acetone.
Didier et al in U.S. Pat. No. 7,241,907 describes a crystalline form as acetone solvate of dimethoxy-docetaxel or 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and its process for preparation by crystallization from an aqueous/acetone solution.
Billot Pascal et al in U.S. 20110144362 A1 appears to cover many crystalline forms, which include crystalline forms as anhydrides, solvates and ethanol hetero-solvates and hydrate forms of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. The disclosure in this application provides nearly 11 new polymorphic forms-which include five (5) new crystal forms of Cabazitaxel anhydrous material designated as Form B, C, D, E, F, which are characterized by—Form B-DSC MP. 150° C., Form C-DSC MP. 146° C., Form D-DSC MP. 175° C., Form E-DSC MP. 157° C. and Form F-DSC MP. 148° C. along with their characteristic XRPD pattern.
U.S. 20110144362 A1 also disclosed four new crystal forms of ethanolate and heterosolvate of Cabazitaxel designated as Form B Ethanolate, Form D Ethanolate, Form E Ethanolate, and Form F Ethanolate/Water Heterosolvate.
Two New Hydrate Forms of Cabazitaxel which include Form C as Monohydrate and Form C as Dihydrate are also part of the disclosure. This patent specification also mentioned that only Form D anhydrous is highly stable, even more stable than acetone solvate form (Form A). This patent application further discloses that other solvates with solvents DCM/DIPE/nPA/IPA/Toluene/MIBK/THF/DMF etc.) were also prepared.
Perhaps polymorphism is known to be unique phenomenon in solid materials, wherein existence of different physical forms including shape, size, and arrangement of molecules in the physical state or polymorphs of same compound are known in the nature. A single compound, or a salt complex, may give rise to a variety of solids having distinct physical properties, which often results in 25. substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Due to this reason, since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all possible polymorphic forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances. However, the existence, and possible numbers, of polymorphic forms for a given compound cannot be predicted. In addition, there are no “standard” procedures that can be used to prepare different polymorphic forms of a substance. Further, it is often unclear for a chemical entity-whether any polymorphism exists in the molecule or not.
New forms of pharmaceutically active/useful compounds provide an opportunity to improve the drug performance characteristics of such product. Further, discovery of additional polymorphic forms may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. Therefore, there exists a need for preparing new forms of a drug substance and processes for preparation thereof.
Though the review of the above mentioned literature disclose diverse polymorphic crystalline forms and processes for the preparation of Cabazitaxel and its solvates, but due to one or more reasons most of them are not particularly convenient and amenable to industrial scale-up for preparing Cabazitaxel and its solvates. Thus, there is an apparent need of a new stable and usable form and its process for preparation, which may be cost-effective, industrially amenable and may overcome the drawbacks of various prior disclosed processes, e.g., multiple solvent combinations as well as multiple steps, which make these processes neither cost effective nor amenable to scale up for industrial scale production. According to the present invention there are provided non solvate amorphous form of Cabazitaxel and process for preparation thereof.